Gulyás Balázs, Sovago Judit, Gomez-Mancilla Baltazar, Jia Zhisheng, Szigeti Csaba, Gulya Károly, Schumacher Martin, Maguire Ralph Paul, Gasparini Fabrizio, Halldin Christer
Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institute, 171 76, Stockholm, Sweden,
Brain Struct Funct. 2015 Sep;220(5):3043-51. doi: 10.1007/s00429-014-0812-y. Epub 2014 Jun 28.
Group 1 metabotropic glutamate subtype 5 receptors (mGluR5) contribute to the control of motor behavior by regulating the balance between excitation and inhibition of outputs in the basal ganglia. The density of these receptors is increased in patients with Parkinson's disease and motor complications. We hypothesized that similar changes may occur in Huntington's disease (HD) and aimed at testing this hypothesis in a preliminary experimental series in postmortem human brain material obtained from HD patients. Using autoradiography, we analyzed mGluR5 density in the putamen, caudate nucleus and cerebellum (control region) in postmortem tissue samples from three patients with HD and three controls with two mGluR5-specific radioligands ([(3)H]ABP688 and [(11)C]ABP688). The density of enkephalin (Enk)- or substance P (SP)-containing neurons was assessed using immunohistochemical and cell-counting methods. [(3)H]ABP688 binding in HD was reduced in the caudate (-70.4 %, P < 0.001), in the putamen (-33.3 %, P = 0.053), and in the cerebellum (-8.79 %, P = 0.930) vs controls. Results with [(11)C]ABP688 were similar; there was good correlation between [(11)C]ABP688 and [(3)H]ABP688 binding ratios. Total cell density was similar in all three brain regions in HD patients and controls. Neuronal density was 69 % lower in the caudate (P = 0.002) and 64 % lower in the putamen (P < 0.001) of HD patients vs controls. Both direct and indirect pathways were affected, with ≥ 90 % decrease in the density of Enk- and SP-containing neurons in the caudate and putamen of HD patients vs controls (P < 0.001). In contrast to earlier observations in PD, in HD, compared to controls, the mGluR5 density was significantly lower in the caudate nucleus. The decrease in neuronal density suggests that neuronal loss was largely responsible for the observed decrease in mGluR5.
第一组代谢型谷氨酸受体5（mGluR5）通过调节基底神经节输出的兴奋与抑制之间的平衡，对运动行为的控制起作用。帕金森病患者及其运动并发症患者体内这些受体的密度会增加。我们推测亨廷顿舞蹈病（HD）可能也会发生类似变化，并旨在通过对取自HD患者的尸检人脑组织进行初步实验系列来验证这一假设。我们使用放射自显影技术，用两种mGluR5特异性放射性配体（[（3）H]ABP688和[（11）C]ABP688）分析了3例HD患者和3例对照者的尸检组织样本中壳核、尾状核和小脑（对照区域）的mGluR5密度。使用免疫组织化学和细胞计数方法评估含脑啡肽（Enk）或P物质（SP）的神经元密度。与对照相比，HD患者尾状核中[（3）H]ABP688结合减少了70.4%（P<0.001），壳核中减少了33.3%（P=0.053），小脑中减少了8.79%（P=0.930）。[（11）C]ABP688的结果相似；[（11）C]ABP688与[（3）H]ABP688结合率之间有良好的相关性。HD患者和对照者所有三个脑区的总细胞密度相似。与对照相比，HD患者尾状核中的神经元密度降低了69%（P=0.002），壳核中的神经元密度降低了64%（P<0.001）。直接和间接通路均受影响，与对照相比，HD患者尾状核和壳核中含Enk和SP的神经元密度降低了≥90%（P<0.001）。与帕金森病早期观察结果相反，在HD中，与对照相比，尾状核中的mGluR5密度显著降低。神经元密度的降低表明神经元丢失在很大程度上是观察到的mGluR5降低的原因。
